The purpose of this proposal is to develop and establish a National Cooperative Drug Discovery Group for the Treatment of Mood Disorders (NCDDG-MD) between investigators in the Center for Neurobiology and Behavior at the University and in the Division of Neuropharmacology at Wyeth Research Laboratory. The goal of this program is to provide a critical advance in drug discovery for mood disorders by focusing and combining the expertise of investigators from each institution on a problem of mutual interest and importance to the field. The program foundation emerges from morphological and molecular evidence that prolonged exposure to stress and depression produces neuronal atrophy and that chronic administration of antidepressant drugs to animals produce changes in neuronal proliferation and molecular markers for neurotrophic factors in the hippocampus that has only been discovered recently. These morphological effects may be key physiological elements that produce or sustain behavioral recovery during remission after chronic administration of antidepressants to patients. The focus of the NCDDG research program will be to develop this key idea as a paradigm for drug discovery in mood disorders. This will be done by establishing that the functional consequences of changes in neuroplasticity produced by chronic antidepressant drug treatment are important for the reversing the detrimental effects of stress on neural remodeling and sustaining behavioral recovery. The experimental program will examine the relationship between the morphological and behavioral consequences of multiple types of antidepressant drug treatments given to rats and mice exposed to stressors that have been demonstrated to be relevant for measuring antidepressant drug responses. Secondly, critical hypotheses concerning the functional relationship between hippocampal cell proliferation and the behavioral consequences of antidepressant drug treatments will be tested by employing novel genetic models. Finally, potentially novel classes of antidepressant drugs will be tested using the developed procedures. Because stress may contribute to the pathophysiology of mood disorders by causing neuronal atrophy and altering cell morphology, increased neurogenesis could contribute to the actions of antidepressant treatment by facilitating neural plasticity and remodeling critical for behavioral recovery from stress. The development of protocols demonstrating that reversal of the functional consequences of neuronal remodeling in animals subjected to stress leads to behavioral recovery will enable the discovery of potentially novel antidepressant drugs. [unreadable] [unreadable]